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Cognitive flexibility and cognitive stability : neural and behavioral correlates in men and mice
(2014)
The ability to flexibly adjust behavior according to a changing environment is crucial to ensure a species' survival. However, the successful pursuit of goals also requires the stable maintenance of behavior in the face of potential distractors. Thus, cognitive flexibility and cognitive stability are important processes for the cognitive control of behavior. There is a large body of behavioral and neuroimaging research concerning cognitive control in general, but also specifically on cognitive flexibility and cognitive stability, albeit most often assessed in separate task paradigms. Nevertheless, whether cognitive flexibility and cognitive stability depend upon separate or shared neuronal bases is still a matter of debate. Complementing empirical research, computational models have become an important strategy in neuroscientific research, as they have the potential of providing mechanistic explanations of empirical observations, for example by allowing for the direct manipulation of molecular parameters in simulated neural networks. The computational model underlying the so-called Dual-State Theory contains specific hypotheses with respect to cognitive flexibility and cognitive stability. The neural networks simulated by this model exhibit multiple stable firing states, i.e., the neural network can maintain a high firing state also without continuing external input due to a network architecture consisting of recurrently connected neurons. Transitions between such network states, also called attractor states, can be induced by external input, and represent working memory contents or active task rules. Simulations showed that the stability of these attractor states, and thus of task rule representations, depend on the dopamine state of the system and can consequently vary between persons. The Dual-State Theory predicts an antagonistic relationship between cognitive flexibility and cognitive stability, as robust attractor states would facilitate the inhibition of distractors, but impair efficient task switching, while rather unstable attractor states would promote efficient transitions between representations but would also come at the cost of increased distractibility.
Based on the Dual-State Theory, a task paradigm was designed allowing for the simultaneous assessment of cognitive flexibility, in the sense of rule-based task switching, and cognitive stability, in the sense of inhibiting irrelevant distractors. Furthermore, a behavioral measure was developed to assess the individual attractor state stability, named spontaneous switching rate (SSR). In the first study of this work, this paradigm was tested in a sample of healthy human subjects using functional magnetic resonance imaging (fMRI). An overlapping fronto-parietal network was activated for both cognitive flexibility and cognitive stability. Furthermore, behavioral as well as neuroimaging results are in favor of an antagonistic relationship between cognitive flexibility and cognitive stability. A specific prefrontal region, the inferior frontal junction (IFJ), was implied to potentially contain the relevant neural networks mediating the transitions between attractor states, i.e., task rule representations, as its activity was modulated by the SSR such that persons with rather unstable attractor states activated it less during task switching while showing better performance. Most importantly, functional connectivity of the IFJ was antagonistically modulated by the SSR: more flexible persons connected it less to another prefrontal area during task switching, while showing higher functional connectivity during distractor inhibition.
In a second study, a larger human sample was assessed and further hypotheses derived from the Dual-State Theory on variability of neural processing were tested: we hypothesized that persons with high brain signal variability should have less stable network states and thus benefit on tasks requiring cognitive flexibility but suffer from it when the task requires a higher degree of cognitive stability. Furthermore, recent fMRI-research on brain signal variability revealed beneficial effects of higher brain signal variability on cognitive performance in general. Using a novel customized analysis pipeline to measure trial-to-trial fMRI-signal variability, we indeed found differential effects of brain signal variability: higher levels of brain signal variability were found to be beneficial for effectiveness, i.e., performance in terms of error rates, for both cognitive flexibility and stability. However, brain signal variability impaired the efficiency in terms of response times of inhibiting distractors, i.e., cognitive stability.
Due to further predictions of the Dual-State Theory concerning schizophrenia and the dopaminergic system, it was considered valuable to pursue a translational approach and thus allowing for the employment of animal models of psychiatric diseases. Consequently, in a first step the human paradigm was translated for a murine population using an innovative touchscreen approach. Results showed analogous behavioral effects in wildtype mice as before in healthy humans: the antagonistic relation between cognitive flexibility and cognitive stability was replicated and also for mice, a behavioral measure for the individual attractor stability was established and validated, named the individual spontaneous switching score.
To conclude, we established a novel paradigm assessing both cognitive flexibility and stability simultaneously showing an antagonistic relationship between these two cognitive functions on the behavioral level in two different species, which supports predictions from the Dual-State Theory. This was further underlined by evidence on the activation, functional connectivity and signal variability level in the human brain.
Local protein synthesis has re-defined our ideas on the basic cellular mechanisms that underlie synaptic plasticity and memory formation. The population of messenger RNAs that are localised to dendrites, however, remains sparsely identified. Furthermore, neuronal morphological complexity and spatial compartmentalisation require efficient mechanisms for messenger RNA localisation and control over translational efficiency or transcript stability. 3’ untranslated regions, downstream from stop codons, are recognised for providing binding platforms for many regulatory units, thus encoding the processing of the above processes. The hippocampus, a part of the brain involved in the formation, organisation and storage of memories, provides a natural platform to investigate patterns of RNA localisation. The hippocampus comprises tissue layers, which naturally separate the principle neuronal cell bodies from their processes (axons and dendrites). Identifying the full-complement of localised transcripts and associated 3’UTR isoforms is of great importance to understand both basic neuronal functions and principles of synaptic plasticity. These findings can be used to study the properties of neuronal networks as well as to understand how these networks malfunction in neuronal diseases.
Here, deep sequencing is used to identify the mRNAs resident in the synaptic neuropil in the hippocampus. Analysis of a neuropil data set yields a list of 8,379 transcripts of which 2,550 are localised in dendrites and/or axons. Using a fluorescent barcode strategy to label individual mRNAs shows that the relative abundance of different mRNAs in the neuropil varies over 5 orders of magnitude. High-resolution in situ hybridisation validated the presence of mRNAs in both cultured neurons and hippocampal slices. Among the many mRNAs identified, a large fraction of known synaptic proteins including signaling molecules, scaffolds and receptors is discovered. These results reveal a previously unappreciated enormous potential for the local protein synthesis machinery to supply, maintain and modify the dendritic and synaptic proteome.
Using advances in library preparation for next generation sequencing experiments, the diversity of 3’UTR isoforms present in localised transcripts from the rat hippocampus is examined. The obtained results indicate that there is an increase in 3’UTR heterogeneity and 3’UTR length in neuronal tissue. The evolutionary importance of the 3’UTR diversity and correlation with changes in species,tissue and cell complexity is investigated. The conducted analysis reveals the population of 3’UTR isoforms required for transcript localisation in overall neuronal transcriptome as well as the regulatory elements and binding sites specific for neuronal compartments. The configuration of poly(A) signals is correlated with gene function and can be further exploit to determine similar mechanisms for alternative polyadenylation.
Usage of custom specified methods for next-generation sequencing as well as novel approaches for RNA quantification and visualisation necessitate the development and implementation of new downstream analytic methods. Library methods for data-mining transcripts annotation, expression and ontology relations is provided. Usage of a specialised search engine targeting key features of previous experiments is proposed. A processing pipeline for NanoString technology, defining experimental quality and exploiting methods for data normalisation is developed. High-resolution in situ images are analysed by custom application, showing a correlation between RNA quantity and spatial distribution. The vast variety of bioinformatic methods included in this work indicates the importance of downstream analysis to reach biological conclusions. Maintaining the integrability and modularity of our implementations is of great priority, as the dynamic nature of many experimental techniques requires constant improvement in computational analysis.
In vitro investigation of genes identified by genome-wide association studies of Parkinson's disease
(2014)
A measurement of the transverse momentum spectra of jets in Pb-Pb collisions at sNN−−−√=2.76 TeV is reported. Jets are reconstructed from charged particles using the anti-kT jet algorithm with jet resolution parameters R of 0.2 and 0.3 in pseudo-rapidity |η|<0.5. The transverse momentum pT of charged particles is measured down to 0.15 GeV/c which gives access to the low pT fragments of the jet. Jets found in heavy-ion collisions are corrected event-by-event for average background density and on an inclusive basis (via unfolding) for residual background fluctuations and detector effects. A strong suppression of jet production in central events with respect to peripheral events is observed. The suppression is found to be similar to the suppression of charged hadrons, which suggests that substantial energy is radiated at angles larger than the jet resolution parameter R=0.3 considered in the analysis. The fragmentation bias introduced by selecting jets with a high pT leading particle, which rejects jets with a soft fragmentation pattern, has a similar effect on the jet yield for central and peripheral events. The ratio of jet spectra with R=0.2 and R=0.3 is found to be similar in Pb-Pb and simulated PYTHIA pp events, indicating no strong broadening of the radial jet structure in the reconstructed jets with R<0.3.
Evolutionary genetics of bears and red foxes over phylogenetic and phylogeographic time scales
(2014)
Climatic fluctuations during the Pleistocene (2.6-0.01 million years) have played an important role during evolution of many species. Cyclic range contractions and expansions had demographic consequences within species, provided environmental conditions for population divergence and speciation and enabled secondary contact and interspecific hybridization. These and other evolutionary processes have left genetic signatures in the genomes of affected organisms. Comprehensive and unbiased estimates of evolutionary processes can be obtained using genetic markers from different parts of the genome and by integrating population genetic and phylogenetic concepts.
Suitable for studies on evolutionary processes and patterns over different evolutionary time scales are bears (Ursidae) and foxes (Vulpes), which occupy a wide range of habitats and evolved during the past few millions of years. In my thesis, I therefore used bears and red foxes as study species to investigate the genetic variation within and between species and to obtain estimates of evolutionary relationships and divergence times of populations and species that I interpreted in a climatic context. Further, I investigated population genetic processes during the evolution of bears. My thesis includes three publications and one submitted manuscript, spanning different evolutionary time scales - from evolutionary relationships and processes among species (phylogenetic time scales, Publications I & II), among populations and closely related species in a geographical context (phylogeographic time scales, Publications II & III), to ongoing processes within species (population genetic time scales, Publication IV).
In Publication I (Kutschera et al. 2014, Mol Biol Evol 31(8):2004-2017), I studied bears at several nuclear markers from several individuals per species, complemented with markers from the Y chromosome. Using approaches based on a population genetic concept (coalescent theory) I obtained a species tree with divergence time estimates. Further, I studied two evolutionary processes in bears, interspecific gene flow and incomplete lineage sorting (ILS). This study contributed to the growing evidence that population genetic processes can be relevant on time scales up to several millions of years.
In Publication II (Hailer, Kutschera et al. 2012, Science 336(6079):344-347), we complemented previous mitochondrial (mt) DNA-based inference of the evolutionary history of polar and brown bears with nuclear DNA. Coalescence-based species tree analyses of multiple nuclear markers from several individuals per species placed polar bears as sister lineage to brown bears and their divergence time to about 600 thousand years ago (ka). This contrasted previous mtDNA-based inference. We explained this discrepancy between mtDNA and nuclear DNA with interspecific gene flow between polar and brown bears.
In Publication III (Kutschera et al. 2013, BMC Evol Biol 13:114), I studied range-wide phylogeographic events and their timing in red foxes. A synthesis of newly generated and published mtDNA sequences was analyzed using a coalescence-based approach with multiple fossil calibration points. Thereby, I validated the identity and geographic distribution of several red fox lineages and showed that red foxes colonized North America and Japan several times independently during the late Pleistocene (126-11 ka) and around the last glacial maximum (26.5-19 ka). In a comparison of my results from red foxes to brown bears and grey wolves, I identified similar phylogeographic patterns.
In Publication IV (Kutschera et al., submitted to Biol Conserv), I found similar levels of genetic variability in vagrant polar bears that had reached Iceland compared to established subpopulations from across the range. Based on climate projections reported by the Intergovernmental Panel on Climate Change in 2014, polar bear habitat will markedly decline and become increasingly fragmented within the next decades. Dispersal will play an important role by connecting isolated subpopulations, thereby maintaining genetic diversity levels. My results indicate that vagrants could stabilize genetic variability when immigrating into established subpopulations.
In conclusion, my thesis provided a deeper understanding of evolutionary genetic processes and patterns and their timing in bears and red foxes in a climatic context, which can have conservation implications. Further, I showed that processes like ILS and interspecific gene flow can be relevant over different time scales and are important aspects of evolutionary history. Thereby, my thesis contributed to the knowledge on the evolutionary history of several carnivore species and on evolutionary processes acting within and between closely related species.
This study investigates the diabetes-associated alterations present in cardiac mesenchymal cells (CMSC) obtained from normoglycemic (ND-CMSC) and type 2 diabetic patients (D-CMSC), identifying the histone acetylase (HAT) activator pentadecylidenemalonate 1b (SPV106) as a potential pharmacological intervention to restore cellular function. D-CMSC were characterized by a reduced proliferation rate, diminished phosphorylation at histone H3 serine 10 (H3S10P), decreased differentiation potential, and premature cellular senescence. A global histone code profiling of D-CMSC revealed that acetylation on histone H3 lysine 9 (H3K9Ac) and lysine 14 (H3K14Ac) was decreased, whereas the trimethylation of H3K9Ac and lysine 27 significantly increased. These observations were paralleled by a downregulation of the GCN5-related N-acetyltransferases (GNAT) p300/CBP-associated factor and its isoform 5-α general control of amino acid synthesis (GCN5a), determining a relative decrease in total HAT activity. DNA CpG island hypermethylation was detected at promoters of genes involved in cell growth control and genomic stability. Remarkably, treatment with the GNAT proactivator SPV106 restored normal levels of H3K9Ac and H3K14Ac, reduced DNA CpG hypermethylation, and recovered D-CMSC proliferation and differentiation. These results suggest that epigenetic interventions may reverse alterations in human CMSC obtained from diabetic patients.
Cytokine-regulated GADD45G induces differentiation and lineage selection in hematopoietic stem cells
(2014)
The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.
Use of drug-eluting balloon coronary intervention prior to living donor kidney transplantation
(2014)
Background: Kidney transplantation is the gold standard of therapy in patients with terminal renal insufficiency. Living donor transplantation is a well-established option in this field. Enlarging the donor's pool implicates the acceptance of an increased rate of comorbidities. Among them, coronary artery disease is a growing problem. An increasing number of patients, undergoing living donation, receive antiplatelet therapies due to coronary disease.
Case presentation: Here we report about the perioperative treatment with a drug-eluting balloon in a patient with major cardiac risk factors who underwent kidney transplantation.
Conclusion: At the current time no recommendation can be given for the routine use of drug-eluting balloons.
We study the effect of weakening creditor rights on distress risk premia via a bankruptcy reform that shifts bargaining power in financial distress toward shareholders. We find that the reform reduces risk factor loadings and returns of distressed stocks. The effect is stronger for firms with lower firm-level shareholder bargaining power. An increase in credit spreads of riskier relative to safer firms, in particular for firms with lower firm-level shareholder bargaining power, confirms a shift in bargaining power from bondholders to shareholders. Out-of-sample tests reveal that a reversal of the reform's effects leads to a reversal of factor loadings and returns.